EP2338473A1

EP2338473A1 - Pharmaceutical dosage forms of tizanidine and administration routes thereof

Info

Publication number: EP2338473A1
Application number: EP20090425528
Authority: EP
Inventors: Massimiliano Borsa
Original assignee: MDM SpA
Current assignee: MDM SpA
Priority date: 2009-12-18
Filing date: 2009-12-18
Publication date: 2011-06-29
Anticipated expiration: 2029-12-18
Also published as: EP2338473B1; EP2338473B9; ES2596359T3; PL2338473T3

Abstract

Pharmaceutical composition in liquid dosage form which contains tizanidine hydrocloride aquous solution suitable for the parenteral, intranasal and oral route administration, is described.

Description

State of the art

Tizanidine, 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothia-diazol-4-amine, is a α₂-adrenergic agonist structurally related to clonidine. It is a centrally acting skeletal muscle relaxant that acts mainly at spinal and supraspinal levels to inhibit excitatory interneurones. It is indicated for the symptomatic relief of spasticity associated with multiple sclerosis or spinal cord injury or disease or painful muscle spasm.
The compound tizanidine, as hydrochloride, is included in Japan and US Pharmacopoeias and it is approved and marketed worldwide, as base, in the form of 2 or 4 mg tablets. As such, tizanidine is usually well and rapidly absorbed by oral route, but it undergoes extensive first-pass effect which inactivates metabolites. The pharmacokinetic profile of tizanidine, T_max 1-2h, T_1/2z 1-2h, suggested to perform slow-release dosage forms as in US 2008 0214629A1 or WO 2008 047208A1 , but, on the other hand, the entity of the first-pass effect, suggested to replace oral absorption with different routes of administration.
Are known in the art patent documents which describe pharmaceutical formulations containing tizanidine: trans-dermal formulations are described in DK 175982B1 , buccal spray formulations are described in WO 2004 019905A1 , buccal and sublingual formulations are described in WO 2004 043431A1 and in US 2004 0122065A1 . The aim of these documents is to increase the onset of action of tizanidine as well as its bioavailability and to reduce the relative hepatic first-pass effect.
Pharmacological papers reported the administration of tizanidine by intramuscular (IM) or intrathecal route to assess its mechanism of action and compare its potency with standard drugs (J. Neurosurg 2004, 101(4):641-7; J. Pharmacol Sci. 2005, 99(1):52-60; Anesthesiology 2003, 98(6):1480-3; Anesth. Analg. 2003, 96(3):776-82; Anesth.

Description of the invention

It is the object of the present invention a pharmaceutical composition in liquid dosage form which contains as active principle the α₂-adrenergic agonist compound Tizanidine.
According to the invention it has been found that tizanidine, in the form of the corresponding hydrochloride, is soluble in water at concentrations and pH suitable for systemic administration, specifically for parenteral, intranasal and oral administration, and that these aqueous solutions of tizanidine hydrochloride may be normally stored and, in addition, easily sterilized by heat so that the use of preservative agents can be, when preferred, avoided.
Pharmaceutical compositions of tizanidine in liquid form, such as the aqueous solutions of the present invention, offer different advantages: they can be administered by parenteral route, i.e. intramuscular (IM), intravenous (IV), or intrathecal route, thus overcoming the first-pass effect; they can be administered by oral route (PO) to fulfil the individual required dose according to the specific pathology; they can be administered by intranasal route (IN) to increase the bioavailability overcoming the hepatic first-pass effect and/or to shorten the time to peak. The transmucosal nasal delivery, represents a delivery option for drugs with limited oral bioavailability due to the degradation in the intestinal tract, such as proteins, or hepatic first-pass metabolism, and is also a convenient alternative to intravenous or intramuscular drug administration. The considerable blood flow, actually responsible for breath conditioning, benefits from the efficient systemic drug uptake and provides direct access to the systemic circulation for transmucosal adsorbed drug.
In accordance with the specific administration route to be used, the composition of the invention may also contain suitable, commonly used agents such as pH buffer, preservative, flavouring, absorption enhancer and hyperbaric agents.
Among commonly used suitable pH buffer agents, aqueous buffer acetate and aqueous buffer phosphate solutions are preferred. Among the commonly used preservative agents, benzyl chloride, methyl-, ethyl- and propylparahydroxybenzoate are preferred. Among commonly used water soluble flavouring agents citrus, preferably orange, eucalyptol, eucalyptus oil and peppermint are preferred. Among commonly used absorption enhancer agents chitosan, methylpyrrolidone and cholic acid are preferred. Suitable tonicity of solutions may be obtained by addition of saline or salt solutions.
The amount of tizanidine, as base, contained in the composition of the invention, which can be daily administered to a patient, may vary in a large range and depends on various factors, such as the pathology to be treated, the route of administration and relative bioavailability, the age and conditions of the patient.
As to the oral administration, the daily dose of tizanidine, as base, is in the range from 2.00-16.00 mg/day. The pH of the oral aqueous pharmaceutical composition may vary from 4.5 to 6.5 and, usually, preservatives, such as benzyl chloride, methyl-, ethyl- and propylparahydroxybenzoate or similar products and flavouring as citrus, preferably orange, or eucalyptol, eucalyptus oil, peppermint aroma and similar products may also be added thereto.
As to the parenteral administration, the daily dose of tizanidine, as base, is generally included in the range 0.10 - 8.00 mg/day, more precisely, in the range from 2.00 to 8.00 mg/day for the intramuscular administration and from 0.10 to 1.00.mg/day for intrathecal administration. The pH value of the parenteral aqueous pharmaceutical composition, precisely for intramuscular administration, may vary from 4.6 to 5.8 and for intrathecal administration it may vary from 5.0 to 5.5. Parenteral aqueous pharmaceutical compositions for intrathecal administrations may also contain suitable hyperbaric agents, optionally containing glucose, as enhancer of the drug penetration. As for the intranasal administration, the daily dose of tizanidine, as base, is generally in the range 6.00 -12.00 mg/day. The pH value of the intranasal aqueous pharmaceutical composition may vary from 4.8 to 7.4. Tizanidine intranasal administrations may contain absorption enhancer agents such as chitosan, methylpyrrolidone or cholic acid and preservative agents such as benzyl chloride, methyl-, ethyl- and propylparahydroxybenzoate or similar products and flavouring compounds as citrus, preferably orange, eucalyptol, eucalyptus oil or peppermint aroma and similar products.
The compositions containing tizanidine hydrochloride aqueous solutions of the present invention, that is the compositions suitable for oral, parenteral and intranasal administration, proved to be well tolerated at the administration site, and showed themselves to be effective for relief both of muscle spasm and of multiple sclerosis and neuronal spasticity. They can be administered over a wide range of doses according to the pathology, route of administration, bioavailability, and peak time. Detailed formulations and physico-chemical properties properly tailored for the different route of administration are hereinafter provided.

Parenteral solution for urgency or intrathecal administration

Intramuscular administration: solution containing 2.29 mg/mL of tizanidine HCl, equal to 2.00 mg of tizanidine base, without any preservative.
Intrathecal administration: solution containing 0.1145 - 1.45 mg/mL of tizanidine HCl, equal to 0.10 - 1.00 mg of tizanidine base, without any preservative, both normal and hyperbaric solution.

Perorally solutions

Aqueous solution at 2.29 mg/mL suitable to be dispensed as 10/20 drops or 0.5/1 mL solution to be diluted with water, equal to 1.00 or 2.00 mg of tizanidine base. Aqueous solution at 4.58 mg/mL suitable to be dispensed as 10/20 drops or 0.5/1 mL solution to be diluted with water, equal to 2.00 or 4.00 mg of tizanidine base. Aqueous solution at 9.16 mg/mL suitable to be dispensed as 10/20 drops or 0.5/1 mL solution to be diluted with water, equal to 4.00 or 8.00 mg of tizanidine base. Drinkable solutions at 0.5725 mg/mL suitable to be dispensed as single dose bottle or sachet containing 4.00 or 8.00 mL, equal to 2.00 or 4.00 mg of tizanidine base. Drinkable solutions at 2.29 mg/mL suitable to be dispensed as single dose bottle or sachet containing 4.00 or 8.00 mL, equal to 8.00 or 16.00 mg of tizanidine base.

Intranasal solutions

Aqueous solutions, with or without flavour, at 22.90 mg/mL suitable to be dispensed as two 50 µL puff by 0.05 mL snap-on pump, equal to 2 mg of tizanidine base. Aqueous solutions, with or without flavour, at 45.80 mg/mL suitable to be dispensed as two 50 µL puff by 0.05 mL snap-on pump, equal to 4.00 mg of tizanidine base.

Preparation of composition for intramuscular injections

Tizanidine hydrochloride can be dissolved in water, saline or in buffer solution at pH range 4.5 - 6.5, filtered, dispensed in ampoules, and sterilized by heating in autoclave according to the common methods, for instance at 121°C for 15 minutes (see Ph. Eur. 5.1.1). The terminal sterilisation by heat is preferable than the 0.22 µm filtration because it does not need any preservative agent. Simple water solutions are hypotonic due to the low concentration of tizanidine hydrochloride (1.145 or 2.29 mg/mL), therefore it is better to adjust tonicity with saline or buffers to increase local tolerability.

Example 1

2 mL vial containing:
Tizanidine.HCl		2.29 mg
Saline to		2.00 mL

Light yellow and clear solution, pH 5.0.

Example 2

2 mL vial containing:

Tizanidine.HCl 2.29 mg

Acetate buffer pH 4.6

(Ph. Eur.4001400 diluted 1 to 6

with water) to 2.00 mL
Light yellow and clear solution, pH 4.6.

Example 3

1 mL vial containing:

Tizanidine.HCl 1.145 mg

Sodium phosphate buffer pH 5.8

(Ph. Eur. 4002100 diluted 1 to 6 with

water) to 1.00 mL
Light yellow and clear solution, pH 5.8.

Preparation of composition for intrathecal injections

The parenteral administration in the spinal cord may increase the local inhibitory effect on the neurones, and the analgesic effect of the compound. Animal data suggest an equivalent activity of tizanidine and clonidine, by local administration, therefore the concentration for injectables ranges between 0.10 and 1.00 mg/mL. According to the experience of anaesthetic drugs, a hyperbaric solution containing glucose could improve the penetration of the drug into the spinal cord and, by consequence, its efficacy. The formulations for this administration route are single dose, preservative-free solution, sterilized by heat.

Example 4

1 mL vial containing:
Tizanidine.HCl	0.1145 mg
Saline to	1.00 mL

Clear or almost clear solution, pH 5.4
This formulation is ready for use.

Example 5

1 mL vial containing:
Tizanidine.HCl	1.145 mg
Saline to	1.00 mL

Light yellow, clear solution, pH 5.0
This formulation can be diluted with saline accordingly to the prescribed dose.

Example 6

1 mL vial containing:
Tizanidine.HCl	0.1145 mg
5% Glucose solution to	1.00 mL

Clear or almost clear solution, pH 5.5
This formulation is ready for use and is not to be diluted.

Example 7

1 mL vial containing:
Tizanidine.HCl	1.145 mg
5% Glucose solution to	1.00 mL

Light yellow, clear solution, pH 5.0
This formulation is ready for use and is not to be diluted.

Preparation of compositions for oral solutions

Tizanidine.HCl aqueous solutions are, according to the concentration, yellow coloured, transparent, pH 4.8, and without any taste. The solutions require to be preserved from yeast and bacterial grow and the range of natural pH, i.e. between 4.5 and 5.0, suggests, as first choice, methyl p-hydroxybenzoate or a mixture of hydroxybenzoates as preservative since these are effective and chemically stable in this range of pH, and do not react with tizanidine.
Tizanidine solutions are tasteless, and to avoid a second accidental administration, which may happen using multidose forms, a flavour to remind the previous administration is added to the formulations. The single dose unit avoids any risk of overdose.

Example 8

Multidose glass or aluminium container holding:

Tizanidine.HCl 2.29 mg

Methyl p-hydroxybenzoate 1.00 mg

Eucalyptol 4.00 mg

95% Ethanol 0.10 mL

Water to 1.00 mL
Yellow, clear solution, pH 4.8
The single doses, 0.5 mL, containing 1.00 mg of tizadine base, or 1 mL, containing 2.00 mg of Tizanidine base, are dispensed by a dropper or a graduated syringe or a pump.

Example 9

Multidose glass or aluminium container holding:

Tizanidine.HCl 4.58 mg

Methyl p-hydroxybenzoate 1.00 mg

Citrus flavour 10.00 mg

95% Ethanol 0.10 mL

Water to 1.00 mL
Yellow, clear solution, pH 4.9
The single doses, 0.5 mL, containing 2.00 mg of tizadine base, or 1 mL, containing 4.00 mg of Tizanidine base, are dispensed by a dropper or a graduated syringe or a pump.

Example 10

Multidose glass or aluminium container holding:

Tizanidine.HCl 9.16 mg

Methyl p-hydroxybenzoate 1.00 mg

Peppermint aroma 1.00 mg

95% Ethanol 0.05 mL

Water to 1.00 mL
Yellow, clear solution, pH 4.7
The single dose, 0.5 mL, containing 4.00 mg of tizanidine base, or 1 mL containing 8.00 mg of tizanidine base, are dispensed by a dropper or a graduated syringe or a pump.

Example 11

A single dose sealed aluminium sachet containing:

Tizanidine.HCl 2.29 mg

Methyl p-hydroxybenzoate 6.00 mg

Citrus flavour 40.00 mg

95% Ethanol 0.40 mL

Water to 4.00 mL
Light yellow, clear solution, pH 5.6.

Example 12

A single dose sealed aluminium sachet containing:

Tizanidine.HCl 4.58 mg

Methyl p-hydroxybenzoate 12.00 mg

Citrus flavour 80.00 mg

95% Ethanol 0.80 mL

Water to 8.00 mL
Light yellow, clear solution, pH 5.6.

Example 13

A single dose sealed aluminium sachet containing:

Tizanidine.HCl 9.16 mg

Methyl p-hydroxybenzoate 6.00 mg

Citrus flavour 40.00 mg

95% Ethanol 0.40 mL

Water to 4.00 mL
Yellow, clear solution, pH 5.5.

Example 14

A single dose sealed aluminium sachet containing:

Tizanidine.HCl 18.59 mg

Methyl p-hydroxybenzoate 12.00 mg

Citrus flavour 80.00 mg

95% Ethanol 0.40 mL

Water to 8. 00 mL
Yellow, clear solution, pH 5.5.

Preparation of composition of intranasal spray solutions

An aqueous solution of tizanidine.HCl at high concentration, 45.00 mg/mL, and pH 4.8 is tolerated by the nasal mucosa without any local side effect, i.e. redness or pain. The proposed formulations are calculated for a single puff of 50 µL/nostril.

Example 15

Tizanidine.HCl	22.90 mg
Methyl p-hydroxybenzoate	1.00 mg
Eucalyptol	4.00 mg
95% Ethanol	0.40 mL
Water to	1.00 mL

Yellow, clear solution, pH 4.8
The formulation allows administering 1.00 or 2.00 mg of tizanidine base with 1 or 2 puffs.

Example 16

Tizanidine.HCl	45.80 mg
Methyl p-hydroxybenzoate	1.00 mg
Eucalyptol	4.00 mg
95% Ethanol	0.40 mL
Water to	1.00 mL

Yellow, clear solution, pH 4.8
The formulation allows administering 2.00 or 4.00 mg of tizanidine base with 1 or 2 puffs.

Example 17

Tizanidine.HCl	22.90 mg
Benzyl alcohol	10.00 mg
Eucalytptol	4.00 mg
Phosphate buffer pH 7.4 (0.03M) to	1.00 mL

Yellow, clear solution, pH 7.4
The formulation allows administering 1.00 or 2.00 mg of tizanidine base with 1 or 2 puffs.

Example 18

Tizanidine.HCl	22.90 mg
Benzyl alcohol	10.00 mg
Eucalytptol	4.00 mg
Chitosan.HCl	10.00 mg
Phosphate buffer pH 7.4(0.03M) to	1.00 mL

Example 19

Tizanidine.HCl	22.90 mg
Benzyl alcohol	10.00 mg
Eucalytptol	4.00 mg
Cholic acid	14.00 mg
Phosphate buffer pH 7.4(0.03M) to	1.00 mL

Yellow, clear solution, pH 7.4.
The formulation allows administering 1.00 or 2.00 mg of tizanidine base with 1 or 2 puffs.

Pharmacokinetics of tizanidine solutions

Preliminary pharmacokinetic data in rabbits at the dose of 3.00 mg/kg of tizanidine hydrochloride by intranasal (IN), intramuscular (IM), and oral route (PO) were performed to test the intranasal absorption without any enhancer. Tizanidine (IN) is rapidly absorbed with a bioavailability close to that of intramuscular route (IM).

Claims

A pharmaceutical composition of tizanidine for oral, parenteral and nasal administration, characterized by the fact that it contains the active ingredient in its hydrocloride form dissolved in a medium selected from water, saline and buffer solution at a suitable pH value, that the obtained solution, duly sterilized by a heat treatment or additioned with a suitable preservative agent, may be administered as such or, optionally, be additioned with one or more suitable, commonly used flavouring, tonicity, hyperbaric and absorption enhancer agents.
A pharmaceutical composition of tizanidine according to claim 1, characterized by the fact that the pH of the solution is in the range from 4.5 to 7.5.
A pharmaceutical composition of tizanidine for parenteral administration according to claim 1 or 2, characterized by the fact that the sterilization is carried out by a heat treatment.
A pharmaceutical composition of tizanidine for intramuscular administration according to claim 2 or 3, characterized by the fact that it contains tizanidine, as base, at the concentration of from 0.10 to 2.00 mg/mL, at a pH value comprised in the range from 4.5 to 6.5, optionally in the presence of a tonicity agent and/or a hyperbaric agent.
The pharmaceutical composition of tizanidine for intrathecal administration according to claims 2 and 3, characterized by the fact that it contains tizanidine, as base, at the concentration of from 0.10 to 1.00 mg/mL, at a pH comprised in the range from 4.5 to 6.5, optionally in the presence of an agent selected from a tonicity agent and a hyperbaric agent.
The pharmaceutical composition of tizanidine for oral and intranasal administration according to claim 1 or 2, characterized by the fact that it contains a preservative agent selected in the group consisting of benzyl chloride, methylparahydroxybenzoate, ethylparahydroxybenzoate and propylparahydroxybenzoate and a flavouring agent selected from the group of aroma consisting of citrus, eucalyptol, eucalyptus oil and peppermint optionally in the presence of a tonicity agent and/or hyperbaric agent.
The pharmaceutical composition of tizadine for oral administration according to claim 6, characterized by the fact that it contains tizanidine, as base, at the concentration of from 0.10 to 45.00 mg/mL, at a pH value comprised in the range from 4.5 to 6.5, in the presence of saline or glucose.
The pharmaceutical composition of tizanidine for nasal spray administration according to claim 6, characterized by the fact that it contains tizanidine, as base, at the concentration from 20.00 to 40.00 mg/mL, at a pH value comprised in the range from 4.5 to 7.4, in the presence of an absorption enhancer agent selected in the group consisting of chitosan, methylpyrrolidone and cholic acid
The pharmaceutical composition of tizanidine for nasal spray administration according to claim 8, characterized by the fact that the absorption enhancer agent is chitosan.